The present invention relates to the coating of an implantable device. More specifically, this invention relates to a method for selective coating of an intraluminal implantable device, such as a stent or graft.
Occlusion of blood vessels reduces or blocks blood flow. During the course of atherosclerosis, for example, growths called plaques develop on the inner walls of the arteries and narrow the bore of the vessels. An emboli, or a moving clot, is more likely to become trapped in a vessel that has been narrowed by plaques. Further, plaques are common sites of thrombus formation. Together, these events increase the risk of heart attacks and strokes.
Traditionally, critically stenosed atherosclerotic vessels have been treated with bypass surgery in which veins removed from the legs, or small arteries removed from the thoracic cavity, are implanted in the affected area to provide alternate routes of blood circulation. More recently, implantable devices, such as synthetic vascular grafts and stents, have been used to treat diseased blood vessels.
Synthetic vascular grafts are macro-porous vessel-like configurations typically made of expanded polytetrafluoroethylene (ePTFE), polyethylene terephthalate (PET), polyurethane (PU), or an absorbable polymer. Grafts made of ePTFE or PET are very non-wetting materials when introduced into an aqueous environment, causing difficulty in impregnating the materials. In addition, grafts made of ePTFE or PET typically are permanently implanted in the body, while grafts made of an absorbable polymer bioabsorb over time. A graft may be positioned into the host blood vessel as a replacement for a diseased or occluded segment that has been removed. Alternatively, a graft may be sutured to the host vessel at each end so as to form a bypass conduit around a diseased or occluded segment of the host vessel.
Percutaneous transluminal coronary angioplasty (PTCA) is a procedure for treating heart disease in which a catheter assembly having a balloon portion is introduced percutaneously into the cardiovascular system of a patient via the brachial or femoral artery. The catheter assembly is advanced through the coronary vasculature until the balloon portion is positioned across the occlusive lesion. Once in position across the lesion, the balloon is inflated to a predetermined size to radially compress against the atherosclerotic plaque of the lesion to remodel the vessel. The balloon is then deflated to a smaller profile to allow the catheter to be withdrawn from the patient""s vasculature.
Restenosis of the artery commonly develops over several months after the procedure, which may require another angioplasty procedure or a surgical by-pass operation. Restenosis is thought to involve the body""s natural healing process. Angioplasty or other vascular procedures injure the vessel walls, removing the vascular endothelium, disturbing the tunica intima, and causing the death of medial smooth muscle cells. Excessive neoinitimal tissue formation, characterized by smooth muscle cell migration and proliferation to the intima, follows the injury. Proliferation and migration of smooth muscle cells (SMC) from the media layer to the intima cause an excessive production of extra cellular matrices (ECM), which is believed to be one of the leading contributors to the development of restenosis. The extensive thickening of the tissues narrows the lumen of the blood vessel, constricting or blocking blood flow through the vessel.
Intravascular stents are sometimes implanted within vessels in an effort to maintain the patency thereof by preventing collapse and/or by impeding restenosis. Implantation of a stent is typically accomplished by mounting the stent on the expandable portion of a balloon catheter, maneuvering the catheter through the vasculature so as to position the stent at the desired location within the body lumen, and inflating the balloon to expand the stent so as to engage the lumen wall. The stent maintains its expanded configuration, allowing the balloon to be deflated and the catheter removed to complete the implantation procedure. A covered stent, in which a graft-like covering is slip-fit onto the stent, may be employed to isolate the brittle plaque from direct contact with the stent, which is rigid.
To reduce the chance of the development of restenosis, therapeutic substances may be administered to the treatment site. For example, anticoagulant and antiplatelet agents are commonly used to inhibit the development of restenosis. In order to provide an efficacious concentration to the target site, systemic administration of such medication may be used, which often produces adverse or toxic side effects for the patient. Local delivery is a desirable method of treatment, in that smaller total levels of medication are administered in comparison to systemic dosages, but are concentrated at a specific site. Therefore, local delivery may produce fewer side effects and achieve more effective results.
One commonly applied technique for the local delivery of a therapeutic substance is through the use of a medicated implantable device, such as a stent or graft. Because of the mechanical strength needed to properly support vessel walls, stents are typically constructed of metallic materials. The metallic stent may be coated with a polymeric carrier, which is impregnated with a therapeutic agent. The polymeric carrier allows for a sustained delivery of the therapeutic agent.
Various approaches have previously been used to join polymers to metallic stents, including dipping and spraying processes. In one technique, the stent is first formed in a flat sheet, placed in a solution of polyurethane, and heated for a short period of time. Additional polyurethane solution is applied on top of the flat sheet, and the stent is again heated. This process produces a polyurethane film over the surface of the stent, and excess film is manually trimmed away. In one variation of this technique, microcapsules containing therapeutic agents are incorporated into the polyurethane film by adding the microcapsules to the polyurethane solution before heating.
In another technique, a solution is prepared that includes a solvent, a polymer dissolved in the solvent, and a therapeutic agent dispersed in the solvent. The solution is applied to the stent by spraying the solution onto the stent using an airbrush. After each layer is applied, the solvent is allowed to evaporate, thereby leaving on the stent surface a coating of the polymer and the therapeutic substance. Use of this spraying technique to apply a thick coating may result in coating uniformity problems, so multiple application steps are sometimes used in an attempt to provide better coating uniformity.
In yet another coating technique, a solution of dexamethasone in acetone is prepared, and an airbrush is used to spray short bursts of the solution onto a rotating wire stent. The acetone quickly evaporates, leaving a coating of dexamethasone on the surface of the stent.
The above-described methods often have difficulty in applying an even coating on the stent surfaces. One common result when using these spraying or immersion processes is that the aqueous coating tends to collect in crevices, apertures, or cavities in the framework of the stent, resulting in an uneven coating having an uncontrollably variable coating thickness. In particular, an excess amount of coating is often entrained in the angle between two intersecting struts of a stent, which is sometimes called xe2x80x9cwebbingxe2x80x9d or xe2x80x9cpooling.xe2x80x9d The deposition of excessive amounts of therapeutic agents results in a poor surface area to volume ratio relative to conformal coatings. When such a coating experiences uncontrolled drying, drying artifacts may result in drug crystal formation.
The use of multiple applications of a fine, diffuse spray may produce a more controllable, even coating than immersion techniques. However, the diffuse application results in much of the coating substance not coating the stent and instead being released into the air. This inefficient use of the coating substance wastes the coating substance, which may be quite expensive, and increases the exposure of the air brush operator to the coating substance.
In addition, existing methods for coating implantable devices do not provide effective techniques for applying coatings of different substances onto different portions of the surface of the implantable device.
In view of the above, there is a need to provide an improved method for coating medical devices which produces superior coating uniformity and control of the location of the coating without an excessive loss of materials. It is also desirable that the coating method can be used on a variety of implantable devices with aqueous or solvent-based coating substances. In particular, it is desired that therapeutic or bioactive substances, such as compositions of a polymer, solvent, and therapeutic substance, can be used to coat stents.
In accordance with various aspects of the present invention, the invention relates to a method for coating an implantable device. In one embodiment, the method comprises applying a first coating substance on a first portion of a surface of the implantable device, applying a second coating substance on a second portion of a surface of the implantable device, and rotating the implantable device about an axis of rotation. In another embodiment, a first coating substance is applied to an interior surface of a cylindrical implantable device, such as a stent or graft, and a second coating substance is applied to an exterior surface. A centrifuge step is performed so that the first coating substance is preferentially and uniformly applied on the interior surface of the implantable device and the second coating substance is preferentially and uniformly applied on the exterior surface of the implantable device.
Various embodiments of the described method enable highly viscous materials to be coated onto implantable devices. Viscous materials are not usually amenable to conventional coating methods such as dipping or spraying, because of the viscous material""s propensity to accumulate in an uneven layer. However, the addition of a centrifugation step after dipping the implantable device in the viscous coating material can transform the uneven masses into a smooth, even coating.
Embodiments of the method also enable uniform coatings to be applied to implantable devices with improved repeatability, thereby improving coating uniformity between batches of implantable devices. With conventional manually-applied spray-coating techniques, operator error or inconsistency may result in different coating thicknesses between batches of stents. The centrifugation processes can reduce unwanted gross deposition of coating substances and enable high reproducibility of the coating quality.
Embodiments of the method also enable multiple stents to be processed simultaneously. Unlike manually-applied airbrush coating methods, in which stents are coated individually or in small groups, large batches of stents can be simultaneously immersed in the coating solution, simultaneously rotated in the centrifuge device, and simultaneously heated in an oven, thereby increasing throughput.
Embodiments of the method also may improve operator safety when coating implantable devices with hazardous materials. It is generally not desirable to spray coat an implantable device with toxic or radioactive coating substances, because of the increased exposure of the operator to the airborne hazardous coating substance. Dipping and centrifuging the implantable device as described above can decrease the amount of handling required for the coating process, resulting in reduced environmental contamination.
Embodiments of the method may also mitigate defects due to handling of the implantable device. In conventional spray processes, the implantable device is held aloft using one or two clamps or fixtures while the coating substance is sprayed onto the device. The point where these clamps contact the device may be masked from receiving the spray, resulting in defects in the coating. In contrast, the centrifuge container has minimal contact with the implantable device during the centrifuge process.
In another embodiment of the present invention, the invention relates to a drug loaded implantable device comprising two or more coating substances, each of the substances applied to portions of the device. In one embodiment, the portions are exterior surfaces of the device. In yet another embodiment, one of the portions is an exterior surface and another of the portions is an interior surface of the device. Further, one of the substances applied to the device can be a first substance that evenly coats a first portion of the device. Another of the substances can be a second substance that evenly coats a second portion of the device.